The Physiology of Stress: Cortisol and the Hypothalamic-Pituitary-Adrenal Axis

We all know the feeling whether it’s your hands trembling as you flip through a blank exam or trouble sleeping while you worry about approaching deadlines. Stress is an inevitable aspect of life through college and beyond. While everyone understands the symptoms of the stress response, few know the underlying physiological mechanisms. When we probe beneath the surface of our anxiety, an elegant balance of stimuli and responses emerges. This paper will present a broad discussion of stress: how stress is defined, the chemistry and physiology underlying it at the cellular level, and the micro and macro level consequences of the stress response.

Defining Stress

Understanding the biochemical interactions that constitute the stress response requires a definition of stress. In the realm of biology, stress refers to what happens when an organism fails to respond appropriately to threats (1). While the “threats” humans face today often take more benign forms compared to those our hunter-gatherer ancestors faced, they can be equally taxing on our bodies.

Some stress, of course, can be beneficial. The pressure it exerts can be an incentive to accomplish necessary goals. Often, however, stress reaches chronic, harmful levels, and deleterious consequences follow, from compromised immune function to weight gain to developmental impairment (2). The intensity of the stress response is governed largely by glucocorticoids, the primary molecules involved in the stress response. Stress can be ephemeral and beneficial, or it can be long-lasting and harmful, causing suffocation, depression, and paralysis (3). Proper stress management takes on great importance given the wide range of bodily systems impacted by stress hormones.

Neurochemistry of Stress

Schematic diagram of how stress affects the body.

The human stress response involves a complex signaling pathway among neurons and somatic cells. While our understanding of the chemical interactions underlying the stress response has increased vastly in recent years, much remains poorly understood. The roles of two peptide hormones, corticotropin-releasing hormone (CRH) and arginine-vassopressin (AVP), have been widely studied. Stimulated by an environmental stressor, neurons in the hypothalamus secrete CRH and AVP.

CRH, a short polypeptide, is transported to the anterior pituitary, where it stimulates the secretion of corticotropin (4). Consequently, corticotropin stimulates increased production of corticosteroids including cortisol, the primary actor directly impacting the stress response (5). Vasopressin, a small hormone molecule, increases reabsorption of water by the kidneys and induces vasoconstriction, the contraction of blood vessels, thereby raising blood pressure (6). Together, CRH and vasopressin activate the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis comprises the system of feedback interactions among the hypothalamus, pituitary gland, and adrenal glands (7).

In sum, the hypothalamus releases CRH and vasopressin, which activate the HPA axis. CRH stimulates the anterior pituitary to release corticotropin, which travels through the bloodstream to the adrenal cortex, where corticoptropin then upregulates cortisol production. Vasopressin, the other hormone secreted by the hypothalamus, stimulates the cortical collecting ducts of the kidneys to increase reuptake of water, resulting in smaller volumes of urine formed. As the next section will illuminate, corticosteroids such as cortisol act across the entire body to promulgate the stress response (8).

Cortisol: Stress Hormone

Cortisol is a glucocorticoid hormone synthesized from cholesterol by enzymes of the cytochrome P450 family in the zona fasciculata, the middle area of the adrenal cortex (9). Regulated via the HPA axis, cortisol is the primary hormone responsible for the stress response. Expressed at the highest levels in the early morning, cortisol’s main function is to restore homeostasis following exposure to stress (10). The effects of cortisol are felt over virtually the entire body and impact several homeostatic mechanisms. While cortisol’s primary targets are metabolic, it also affects ion transport, the immune response, and even memory.

Cortisol counters insulin by encouraging higher blood sugar and stimulating gluconeogenesis, the metabolic pathway that synthesizes glucose from oxaloacetate. The presence of cortisol triggers the expression of enzymes critical for gluconeogenesis, facilitating this increase in glucose production. Conversely, it also stimulates glycogen synthesis in the liver, which decreases net blood sugar levels (11). In these ways, cortisol carefully regulates the level of glucose circulating through the bloodstream. Cortisol’s beneficial effects are clear from its role in metabolism: during states of fasting, when blood glucose has been depleted, cortisol ensures a steady supply of glucose via gluconeogenesis.

Cortisol’s role in ion regulation, particularly regarding sodium and potassium, has also been widely studied. Cortisol prevents cells from losing sodium and accelerates the rate of potassium excretion. This helps regulates bodily pH, bringing it back into equilibrium after a destabilizing event. Cortisol’s ability to regulate the action of cellular sodium-potassium pumps has even led to speculation that it originally evolved as a sodium transporter (12).

Structure of cortisol.

Cortisol’s weakening effects on the immune response have also been well documented. T-lymphocyte cells are an essential component of cell-mediated immunity. T-cells respond to cytokine molecules called interleukins via a signaling pathway. Cortisol blocks T-cells from proliferating by preventing some T-cells from recognizing interleukin signals. It also stifles inflammation due to inhibition of histamine secretion (13). Cortisol’s ability to prevent the promulgation of the immune response can render individuals suffering from chronic stress highly vulnerable to infection.

A role for cortisol in memory has also been demonstrated. The hippocampus, the region of the brain where memories are processed and stored, contains many cortisol receptors. While normal cortisol levels have no adverse effects on the hippocampus, excess cortisol overwhelms the hippocampus and actually causes atrophy. Studies of the elderly have indicated that those with elevated cortisol levels display significant memory loss resulting from hippocampus damage, but the exact age range at risk is unclear. There is a reprieve, however, for the chronically stressed: the damage incurred is usually reversible (14).

Finally, cortisol participates in an inhibitory feedback loop by blocking the secretion of corticotripin-releasing hormone, preventing the HPA axis interactions central to glucocorticoid secretion. Many in the scientific community speculate that chronic levels of high stress disrupt the delicate feedback balance, resulting in the failure of feedback inhibition to operate and the continued release of cortisol (15).

Sleep Deprivation, Caffeine, and Alcohol All Increase Cortisol

Stressed Dartmouth students often sacrifice sleep while increasing consumption of caffeine and alcohol, all of which impact cortisol levels and thus, the physiological markers of the stress response. While no connection has yet been established linking sleep deprivation to long-term HPA axis activity, acute sleep loss confuses the HPA axis and disrupts negative glucocorticoid feedback regulation (16). Leproult et al. found that plasma cortisol levels were elevated by up to 45 percent after sleep deprivation, an increase that has implications including immune compromise, cognitive impairment, and metabolic disruption (17). These consequences should give pause to anyone contemplating an all-nighter the day before an exam.

The relationships among caffeine, stress, and cortisol secretion will also be of interest to Dartmouth’s caffeinated masses. Repeated doses of caffeine over a single day result in markedly increased cortisol levels, regardless of the stressor involved or the sex of the individual. Although the extent of the link has not been fully elucidated, a positive relationship clearly exists between caffeine intake and cortisol release, and this relationship is exacerbated when other stressors are introduced. Thus, supplementing a lack of sleep with multiple cups of coffee or energy drinks actually reinforces the negative effects of the stress response and further undermines performance. The benefits of caffeine intake must be balanced with its implications for cortisol secretion. (18)

Often, students decide to celebrate after a stressful episode by consuming alcohol, often in large quantities over a short time frame. Ironically, this method of releasing stress actually stimulates the HPA axis and encourages the manufacture and release of cortisol. In fact, the elevation in glucocortioid levels as a result of alcohol consumption can be greater than the elevation from stressful stimuli. Alcohol probably functions to activate the HPA axis by disinhibiting it: alcohol depresses the nerve cells responsible for HPA inhibition, thereby elevating HPA axis activity (19). As a result, the adrenal cortex secretes higher levels of cortisol. It is hardly surprising, then, that Dartmouth students and college students generally complain of the consequences of considerable anxiety and pressure: our common responses to stress, lack of sleep, caffeine intake, and alcohol consumption act in conjunction to raise the amount of cortisol in our bodies, augmenting the very stress we seek to combat.

Stress and Health: Short-Term and Long-Term Effects

Many of us know from experience that stress compromises the immune response, an empirical observation buttressed by our understanding of cortisol’s physiological effects. Indeed, the effects of acute and chronic stress on human health are myriad and severe. During periods of increased stress, “the immune cells are being bathed in molecules which are essentially telling them to stop fighting,” according to Dr. Esther Sternberg (20). These molecules, namely cortisol, suppress the immune system and inflammatory pathways, rendering the body more susceptible to disease.

High levels of stress, even over relatively short periods and in vastly different contexts, tend to produce similar results: prolonged healing times, reduction in ability to cope with vaccinations, and heightened vulnerability to viral infection (21). The long-term, constant cortisol exposure associated with chronic stress produces further symptoms, including impaired cognition, decreased thyroid function, and accumulation of abdominal fat, which itself has implications for cardiovascular health. The bottom line is that both episodes of acute stress and more prolonged stressful circumstances precipitate lower levels of general health, and exposure to such stress should be minimized. In the most extreme cases, Cushing’s Syndrome, characterized by dangerously high cortisol levels, can result. Those afflicted with Cushing’s experience rapid weight gain, hyperhydrosis, and hypercalcemia, along with various psychological and endocrine problems (22).

Conclusion

Stress is unavoidable. Our bodies are designed to react to our environment in an effort to preserve homeostasis. Arming ourselves with an understanding of the mechanisms, agonists, and antagonists of the stress response, however, positions us to minimize stress and its impact on our minds and bodies. It is both a blessing and a curse that the HPA axis evolved to be so sensitive to factors like circadian rhythm, caffeine, and alcohol. We are experts at maintaining homeostasis but often novices at managing stressful circumstances. The good news is that stress levels rest largely on our own behavior and decisions and that we can optimize our bodies’ responses to stress based on how we live our daily lives.

Just so you know, I know about everyone's cognitive problems, since I have them too. I have been unable to speak. Like you tell me. Mouth and Voice no longer connected to the Brain. I know about all of it. 'Been face-stuck to the carpet. 'Been driving in a fugue state, and suddenly woke up having no idea why I was in the car or where I was - what road, or where I was going (it was sunlight so I knew it was daytime). I know ALL ABOUT all these experiences. I dont talk about them, why? BECAUSE YOU HAVE HAD THEM TOO!!! I know this.

I think people are saying these things to me because they would like to be a part of this historical event (it WILL be a different kind of lobbying, trust me), but dont feel confident about the material or that they can do this. Believe me. Me and Beaux, both of us being essentially nerdy, are not great, natural speakers. You know this.

So, I am validating your condition. You dont have to tell me, I know.

But as far as the Lyme crymes? Yes, it's complicated, but you only have to know 2 things: Chronic Lyme illness is like AIDS, or it is the opportunistics that take over. A *new* condition that is the same condition occurred in people who got the Lyme vaccine - chronic systemic illness, that is neuro too, like Chronic Fatigue Syndrome. The bad guys say this is an imaginary symptom set (the Triad: Cognitive/Neuro, Musculoskeletal, Chronic Fatigue/Malaise). And it was caused by the vaccine, OspA, a fungal antigen (we say in the movie it is like injecting bathroom scum, not "like" like, like REALLY like), ...

Because the bad guys knew this, that OspA caused the same "multi-system" disease, they changed the case definition and said, "Oh, No, Lyme is not a new Great Imitator, it's just a bad knee," and "patients feel fine outside their arthritis symptoms" and "seronegative Lyme is a conflict in terms because only the arthritis tests positive" - meaning only the arthritis tests positive, and hardly anyone has such a condition.

So, what do you need to know. TWO THINGS: OspA, is pam3cys and a fungal toxin, and the bad guys *knew* it by 1993 and threw those toxic cases out, and speak now only of bad knees ("Lyme disease"). It's a game. A semantics game. You dont have Lyme disease and I dont have Lyme disease. Why. We have chronic fatigue and dementia, which was excluded by the non-consensus of Dearborn.

See, the crooks WON the Semantics Game because not even any "LLMDs" or ILADs or the LDA or ANY of the non-profits understand this. Our side argues, "Yes, we have Lyme, we found spirochetes."

Why did the criminals of the ALDF perform this crime? They wanted a vaccines and test kits empire and actually used the word "enterprise" about the ALDF dot com in 1998. It was a whole new genre based on "Emerging Infectious Diseases" related to Global Pollution and is the actual name of the CDC's journal.

(CDC has a journal on new diseases caused by global pollution/warming and has had this magazine for many years. To wit, Lyme allegedly came from African Sea Birds blowing over on hurricanes, no really, they say this.)

It's not that complicated, is the point of this post. Lyme was an Imitator that caused nearly every known disease (of course, sepsis does too), ... and then it became only a bad knee because they wanted to sell a fungal toxin as a vaccine that caused the same disease.

People ask me all the time (and I ask them), what do we need to know? Two things: What is OspA such that it caused the disease the CDC staff do not want to admit to any more... and what did they do about it?

(Dearborn).

And that's what we will be lobbying about. What is OspA and what did the bad guys do about it. Steere went to Europe to falsify the testing.

Why did he go to Europe to falsify the testing and use German patients?

So no one could demand to see those results which were probably made up.

About Me

Grew up in a rural area, farming and logging and construction filled my life with many skills. Yet my heart as always followed a simpler life. It has been for the love of nature and all it entails that has led me to happier place full of adventures, great and small, trying never to miss the opportunity to help each and everyone.